Download Statement on cardiopulmonary exercise testing in chronic heart

Statement
Statement on cardiopulmonary exercise testing in chronic
heart failure due to left ventricular dysfunction:
recommendations for performance and interpretation
Part I: Definition of cardiopulmonary exercise
testing parameters for appropriate use in chronic
heart failure
Task Force of the Italian Working Group on Cardiac Rehabilitation Prevention
(Gruppo Italiano di Cardiologia Riabilitativa e Prevenzione GICR) endorsed by
the Working Group on Cardiac Rehabilitation and Exercise Physiology of the
European Society of Cardiology*
Received 17 January 2006 Accepted 18 January 2006
Cardiopulmonary exercise testing (CPET) provides a global assessment of the integrated response to exercise involving
the pulmonary, cardiovascular, haematopoietic, neuropsychological, and skeletal muscle systems. This information cannot
be obtained through investigation of the individual organ systems in isolation. The non-invasive, dynamic physiological
overview permits the evaluation of both submaximal and peak exercise responses, providing the physician with relevant
information for clinical decision making. The use of CPET in management of the chronic heart failure patient is increasing
with the understanding that resting pulmonary and cardiac function testing cannot reliably predict exercise performance
and functional capacity and that, furthermore, overall health status and prognosis are predicted better by indices of
exercise tolerance than by resting measurements. Our aim is to produce a statement which provides recommendations on
the interpretation and clinical application of CPET in heart failure, based on contemporary scientific knowledge and
technical advances: the focus is on clinical indications, issues of standardization, and interpretative strategies for
c 2006 The European Society of Cardiology
CPET. Eur J Cardiovasc Prev Rehabil 13:150–164 European Journal of Cardiovascular Prevention and Rehabilitation 2006, 13:150–164
Keywords: exercise, heart failure, physiology, training
Introduction
The purpose of this statement from the Gruppo Italiano
di Cardiologia Riabilitativa (GICR) endorsed by Working
Group on Cardiac Rehabilitation and Exercise Physiology
of the European Society of Cardiology is to produce a
comprehensive, conceptually balanced document on
the use of cardiopulmonary exercise testing (CPET) in
patients with chronic heart failure (CHF) due to left
ventricular dysfunction.
*
See appendix for details.
Correspondence and requests for reprints to Massimo F. Piepoli, Heart Failure
Unit, Cardiac Department, G da Saliceto Polichirurgico Hospital, Cantone del
Cristo, Piacenza 29100, Italy.
Tel: + 39 0523 303212; fax: + 39 0523 303220;
e-mail: [email protected]
CPET is a well-established tool applied in several clinical
entities [1], and significant overlapping exists in
the exercise responses of patients with different
respiratory and cardiac diseases, the indication, performance and interpretation are peculiar in patients
with CHF.
The aim is to produce a statement that provides
recommendations on the interpretation and clinical
application of CPET in CHF, based on contemporary
scientific knowledge and technical advances: the focus
is on clinical indications, issues of standardization, and
interpretative strategies for CPET. Accordingly,
this document is presented in eight sections: (1)
c 2006 The European Society of Cardiology
1741-8267 Copyright © European Society of Cardiology. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 151
The intended audience for this document includes those
who perform clinical CPET, and those who use the results
of CPET to assist in clinical decision-making and in
the prescription of exercise training programmes.
Particular emphasis has been given to a description of
the indications and applications of CPET in the
diagnostic process, including prognosis, risk stratification
and therapeutic monitoring of CHF patients.
For editorial purposes, this statement has been divided in
three parts, where the first includes the definition, the
second the modality, and the third the interpretation of
the test.
The GICR Ad Hoc Task Force on Cardiopulmonary
Exercise Testing included a group of acknowledged
experts with a broad range of clinical and research
expertise and conceptual approaches to the topic. In this
document, recommendations are based on best available
evidence, current prevailing scientific knowledge and
expert opinion. There is an increasing demand for
diagnostic and prognostic tools to stratify risks, to provide
informed decision making in the timing and choice of
appropriate therapeutic options (including drug, device
and surgical interventions) and rehabilitation programmes
in CHF. CPET provides reproducible indices of exercise
limitation, cardiac and pulmonary function and, as such, it
offers a useful means for both risk stratification and
selection of therapeutic approaches. Increasing use of
CPET has been fuelled by advances in technology,
including the development of automated exercise systems with enhanced data acquisition and management
and subject-monitoring capabilities, combined with
scientific advances in exercise physiology and increased
awareness of the importance of the integrated response in
clinical assessment [2].
To achieve optimal use of this test in clinical practice,
clarification of conceptual issues and standardization of
CPET practices are necessary [3]. CPET use is still very
limited since it is considered a complex methodology
requiring a high level of organization and skilled
processes. Our aim is to increase awareness and use of
CPET, by showing that useful information provided by
this technique is achievable and of value in multiple
clinical settings.
ropsychological, and skeletal muscle systems. This noninvasive, dynamic, physiological assessment permits
the evaluation of both submaximal and peak exercise
responses. It involves the measurement of respiratory
gas exchange: oxygen uptake (VO2), carbon dioxide
output (VCO2) and minute ventilation (VE), in addition
to monitoring electrocardiographic signals, blood pressure
and pulse oximetry, typically during a symptom-limited
maximal progressive exercise tolerance test. Under
steady-state (equilibrium) conditions, VO2 and VCO2
measured at the mouth are equivalent to the total body
O2 consumption and CO2 production.
The clinical meaning and importance of the respiratory
gas exchange parameters with the derived indices are
discussed below.
Oxygen uptake (VO2)
During exercise the relationship between work output,
VO2, heart rate (HR), and cardiac output (CO) is
approximately linear (Fig. 1). VO2 is determined by
cellular O2 consumption and by the rate of O2 transport.
VO2 can be computed from blood flow and O2 extraction
by the tissues (distance between capillary and mitochondria), as expressed in the Fick equation [see also the
section on CO2 output (VCO2) below]:
VCO 2 ¼ CO½CðA VÞO2 diff
ð1Þ
VO 2 ¼ HRSV½CðA VÞO2 diff
ð2Þ
where SV is stroke volume, while C(A – V)O2diff is
arteriovenous O2 difference. Several factors can influence
O2 uptake: (1) oxygen-carrying capacity of the blood
(which is determined by the available haemoglobin (Hb),
the Hb–O2 saturation/dissociation curve which shifts
with temperature, CO2 and pH); (2) cardiac function
Fig. 1
AT
4.0
VO2 (ml/kg per min)
definitions of CPET; (2) indications for CPET in CHF;
(3) safety; (4) equipment; (5) exercise protocols; (6)
modality of performance; (7) data reporting; and (8)
interpretation.
2.0
0.0
R
CPET provides a global assessment of the integrated
response to exercise, allowing a comprehensive evaluation
of the pulmonary, cardiovascular, haematopoietic, neu-
E
0
10
Rest
Definitions of CPET
Peak
Exercise time (min)
Recovery
Oxygen uptake (VO2)–exercise time relationships during maximal
exercise in a patient with moderate chronic heart failure. AT, anaerobic
threshold; E, exercise.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
152 European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
(HR, SV); (3) regional and local distribution of peripheral
blood flow; (4) extraction by the tissues (capillary density,
mitochondrial density and function, adequacy of perfusion, and tissue diffusion). The same factors determining
VO2 in normal patients also determine the response in
CHF patients.
VO2–work rate relationship (VO2 /WR)
Normally, VO2 increases linearly as external work (power
output) increases (Fig. 2). The accurate determination of
the external work rate in watts [or kilopound metres
(kpm) per min] allows the determination of this
relationship. Cycle ergometry allows an accurate measurement of the external work. The slope of VO2 versus
external work rate reflects the metabolic conversion of
chemical potential energy to mechanical work and the
mechanical ability of the musculoskeletal system. The
slope determined from the rate of change in VO2 divided
by the rate of change in external work during incremental
exercise testing on a cycle ergometer (VO2/WR) is
normally about 10–11 ml/min per watt [2] and is independent of sex, age and height.
A reduction in VO2/WR relationship most often indicates
alteration in the metabolism of the skeletal muscles
and/or inadequacies of O2 transport, as may occur
with diseases of the heart, lungs or circulation. Thus this
pattern is not specific for diseases of the heart
(such as CHF), but is also present in diseases of other
organs and systems. It may also reflect errors in
calibration. Nevertheless, since VO2/WR can also be
assessed during submaximal exercise, it may
provide important prognostic information in CHF
patients [4].
In patients with severe CHF, the slope of VO2/WR can be
decreased to 7 or 8 ml/min per watts (Fig. 2) [5]. This is
the reason why it is mandatory to measure VO2 in CHF
patients and not to derive it from peak work-rate, based
on various formula established in normal subjects in
whom the slope is relatively constant. The decrease of
slope is probably related to altered kinetics of cardiac
output increase and/or peripheral oxygen extraction.
In patients undergoing submaximal graded exercise, the
VO2/WR slope provides some insights: a normal slope
suggests a non-cardiac cause to stopping exercise, a
decreased slope suggests circulatory failure. However, at
the individual level, this slope exhibits high variability,
limiting its use. Its prognostic role has been suggested
[6].
VO2max–VO2peak
Based on the above-stated principles [equations (1) and
(2)], it derives that as VO2 increases with increasing
external work, the determinants of VO2 approach maximal
values, and as each factor approaches its relative limits
(e.g. SV, HR or tissue oxygen extraction) the VO2/WR
slope begins to plateau. Achieving a clear plateau in VO2
has traditionally been used as the best evidence of VO2max
(Fig. 3).
VO2 can increase from a resting value of about 3.5 ml/kg
per min (about 250 ml/min in an average individual) to
VO2max values about 15 times the resting value (30–50 ml/
kg per min). VO2max is considered reduced when below
80% of predicted values.
VO2max is the best index of aerobic capacity and the gold
standard for cardiorespiratory fitness. It represents the
maximal achievable level of oxidative metabolism involving large muscle groups. However, in clinical testing
situations, a clear plateau may not be achieved because of
earlier occurrence of intolerable symptoms limiting
exercise [7], when only VO2 at peak exercise can be
measured (VO2peak). Consequently, VO2peak is often used
Fig. 2
VO2
6.0
Normal
3.0
0.0
VCO2
CHF
6.0
2.0
3.0
1.0
VO2
VCO2
2.0
1.0
0.0
0
200
Watt
400
0
50
Watt
100
VO2 and VCO2-work rate relationships in a normal subject (Normal) and in a patient with chronic heart failure (CHF).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 153
Table 1 Predictors of exercise intolerance (VO2peak) or increased
ventilatory response to exercise in chronic heart failure (CHF)
(modified from Piepoli et al. [12])
Fig. 3
VO2
VO2 max
Work rate
Estimation of maximal oxygen uptake (VO2max).
as an estimate for VO2max. For practical purposes, VO2max
and VO2peak are currently used interchangeably, although
they express different physiological measures [8].
Skeletal muscle changes
Muscle atrophy
Muscle strength
Fibre type
I (%)
IIb (%)
Mitochondrial volume density
Oxidative enzymatic activity
PCr rate depletion on exercise
Autonomic changes
Muscle ergoreflex
Peripheral chemoreflex
Central chemoreflex
Carotid baroreflex
LF-HRV
Pulmonary changes
Lung diffusion (TLCO)
Inspiratory capacity
PCWP
Aortic wall elasticity
RVEF > 35
LVEF
Number of
patients
r
P
15
10
– 0.48
0.40
< 0.01
< 0.001
22
22
60
11
25
– 0.81
0.68
0.56
0.68
– 0.62
< 0.01
< 0.01
< 0.001
< 0.05
< 0.01
123
123
123
123
123
– 0.53
– 0.33
– 0.58
0.52
0.60
< 0.005
< 0.05
< 0.003
< 0.02
< 0.001
40
51
51
78
67
763
0.62
0.71
– 0.43
0.39
0.40
0.19
< 0.001
< 0.001
< 0.01
< 0.04
< 0.01
NS
LF-HRV, low-frequency fluctuation of heart rate variability; LVEF, RVEF, left and
right ventricular ejection fraction, respectively; NS, not significant; PCr,
phosphocreatine; PCWP, pulmonary capillary wedge pressure; TLCO, lung
transfer capacity for carbon monoxide.
Aerobic capacity should be measured directly because its
estimation from resting indices, work rate, or submaximal
exercise protocols is limited by physiological mechanisms
and methodological inaccuracies, and as such is unreliable
[8]. In turn, direct measurement of VO2max is reliable and
reproducible in normal subjects [9,10] and in CHF
patients [11]. The main determinants of normal VO2max
or VO2peak are genetic factors and quantity of exercising
muscle. VO2max and VO2peak are also dependent on age, sex
and body size, and can be affected by training. Decreases
in VO2max or VO2peak are general indicators of reduced
exercise capacity [12] (Table 1). Underlying causes of
exercise limitation are determined, in turn, by inspecting
the pattern of the responses of the other variables.
course, poor effort. In addition, in patients, perceptual
responses (symptoms) rather than a physiological process,
as defined in the Fick equation, may be responsible for a
low VO2peak.
Contrary to observations in athletes or fit subjects, what is
measured at the end of exercise in a CHF patient is not a
plateau of VO2max, the patients stop early because of
fatigue or dyspnoea. Therefore, before interpreting the
value of VO2peak, it is necessary to be sure that the test has
been maximal or submaximal, and can be considered valid.
Kinetics of VO2 recovery after exercise
A reduced VO2peak is the starting point in the evaluation
of reduced exercise tolerance. In fact, reduction in
VO2peak may have several causes: it may reflect problems
with oxygen transport (cardiac output, O2-carrying
capacity of the blood), pulmonary limitation (mechanical,
control of breathing or gas exchange), oxygen extraction
at the tissues (tissue perfusion, tissue diffusion),
neuromuscular or musculoskeletal limitations, and, of
In CHF, VO2max and VO2peak are reduced when computed
either as absolute terms (l/min), or weighted terms (ml/
kg per min), or as percentage of normal (with respect to
the predetermined values in relation to age, sex and body
mass index). They constitute one of the best independent prognostic indices [13] (see Part III: Interpretation). Their assessment allows risk stratification, the
choice of the therapeutic regimen and the relative
response (pharmacological and non-pharmacological).
At recovery, VO2 decreases exponentially after a graded
exercise (Fig. 1). The half-time of VO2 recovery (T1/2) has
been shown to be 60–80 s in normal subjects after graded
exercise. The kinetics of VO2 is prolonged with the
severity of heart failure. Patients with a VO2peak < 10–
12 ml/kg per min may need 3 min to decrease their VO2 by
50%. This is probably related to the slow kinetics of
reconstitution of the energetic stores after exercise. This
VO2-off kinetics has the advantage of being only minimally influenced by the level of exercise; therefore, in
case of submaximal exercise (at least when > 50% of
VOmax), the VO2-off kinetics can be used to analyse the
degree of impairment of circulatory function [14]. A
normal VO2-off with a low VO2peak suggests submaximal
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154
European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
exercise. Various groups have also shown that the halftime of VO2 recovery has prognostic value [15].
CO2 output (VCO2)
During exercise, VCO2 is determined by factors similar to
those that govern O2 uptake: cardiac output, CO2carrying capacity of the blood, and tissue exchange are
major determinants. However, because CO2 is much more
soluble in tissues and blood, VCO2 measured at the mouth
is more strongly dependent on ventilation than is VO2. For
example, before the beginning of exercise, if psychogenic
hyperventilation is present, measured VCO2 is higher
than VO2.
During short-duration exercise, glycogen is used primarily
by the muscles for energy, and the relation between O2
consumption and CO2 production is almost equimolar. As
such, during progressive exercise VCO2 increases nearly as
much as does VO2 over the lower work rate range, with an
average VCO2 versus VO2 relationship of slightly less than
1.0 [2].
There is typically a relatively sharp change in slope
toward the midrange of the VO2 response [anaerobic
threshold (AT), determined by V-slope method] (Fig. 4).
This results in a steeper, but typically quite linear, profile
over the upper work rate range. The steeper slope
reflects the CO2 generated in excess of that produced by
aerobic metabolism, due to bicarbonate buffering of
increased lactic acid production at these high work rates.
With anaerobic metabolism, VCO2 increases as a result of
the chemical reaction between hydrogen ions (H + , from
lactate) and dissolved CO2:
Hþ þ HCO
3 $ H2 CO3 $ CO2 þ H2 O
ð3Þ
As tissue lactate production increases [H + ], the reaction
is driven to the right, producing extra CO2 above that
produced aerobically. The excess CO2 may also come
from reduction in the body CO2 stores as a result of
hyperventilation (manifested as arterial hypocapnia).
Since the VE is closely proportionally coupled to VCO2
during exercise, it is useful to analyse VE in relation to
VCO2. It is also important to measure CO2 output
accurately, as it is the basis for the calculation of several
derived variables, including (1) the respiratory exchange
ratio, (2) the ratio between physiological dead space and
tidal volume (VD/VT), and (3) alveolar ventilation.
The mechanisms that govern VCO2 rise in normal patients
are also active in CHF patients. However, for the same
amount of VCO2 produced, the CHF patient presents a
higher VE, and therefore the slope of the relationship of
VE in relation to VCO2 is significantly steeper: the
reference value of 34 is typically surmounted (see the
section on Ventilation, below).
Respiratory exchange ratio (VCO2/VO2)
The ratio of VCO2/VO2 is called the gas exchange ratio
or respiratory exchange ratio (RER). Under steady-state
conditions, the RER equals the respiratory quotient
(RQ), the value of which is determined by the fuels used
for metabolic processes. The term ‘RQ’ is often reserved
for expressing events at the tissue level, which is difficult
to measure and is not determined during clinical exercise
testing. The term ‘RER’ is usually measured by gas
exchange at the mouth.
In steady-state conditions, an RQ of 1.0 indicates
metabolism of primarily carbohydrates, whereas an RQ
of less than 1.0 indicates a mixture of carbohydrates with
fat (RQ about 0.7) or protein (RQ about 0.8). In a true
steady state, the blood and gas transport systems are
keeping pace with tissue metabolism; thus, the RER can
be used as a rough index of metabolic events (RQ).
Fig. 4
Normal
CHF
2.0
VCO2
VCO2
6.0
3.0
0.0
0.0
3.0
VO2
6.0
1.0
0.0
0.0
1.0
VO2
2.0
Anaerobic threshold in a normal subject (Normal) and in a patient with chronic heart failure (CHF).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 155
However, above the anaerobic threshold an RER greater
than 1.0 could also be caused by CO2 derived from lactic
acid or by hyperventilation, because of the 20-fold or
more higher tissue solubility of CO2 compared with O2,
and due to the fact that HCO3– and proteins are
significant forms of transport for CO2 in body tissues,
whereas the only significant form of transport for O2 is by
combination with haemoglobin.
This index provides an indication of the level of exercise
performed during CPET: in cases where a value above 1.1
is not reached the test is usually considered submaximal
[8]. If the patient stops before reaching this value,
limiting factors other than cardiac ones should be
considered. This information may provide important
prognostic value in CHF: an impaired exercise tolerance
(reflected by VO2peak < 10 ml/kg per min) reached during
maximal CPET test (with RQ value > 1.1 at peak
exercise) is associated with a high mortality rate [13].
Anaerobic threshold (AT)
The AT, also known as the lactate threshold, lactic acid
threshold, gas exchange threshold, or ventilatory threshold, is the point at which VE increases disproportionately
relative to VO2 and work. It represents the theoretical
point during incremental exercise when muscle tissue
switches over to anaerobic metabolism as an additional
source: lactic acid begins to accumulate, it is buffered in
the serum by the bicarbonate system, resulting in
increased CO2 excretion, which causes reflex hyperventilation. It is considered an estimator of the onset of
metabolic acidosis caused predominantly by the increased
rate of rise of arterial lactate during exercise, according to
equation (3).
The AT is referenced to the VO2 at which this change
occurs and is expressed as a percentage of the predicted
value of VO2max (%VO2max predicted). It occurs at 50–60%
predicted VO2max in normal, untrained individuals.
Work below AT encompasses most activities of daily
living. It is reduced in most patients with important
cardiovascular disease. An increase in ATwith training can
greatly enhance an individual’s capacity to perform
sustained submaximal activities, with consequent improvement in quality of life.
The difference in the terminology used to describe this
transition reflects the controversy that exists regarding
the physiological mechanisms underlying the increases in
muscle and blood [lactate] that occur at the AT. Although
the classic views concerning the assessment of the AT
have been supported [16,17], others have continued to
question this viewpoint [18,19]. If different muscle
groups reach anaerobic metabolism at different times,
the transition will be smooth and a distinct point, the AT,
may be difficult to determine accurately.
Mechanisms
Controversies exist concerning the processes at the origin
of AT: it is possible that both an imbalance between
oxygen delivery versus oxidative capacity and the pattern
of muscle fibre recruitment, contribute to the increase in
lactic acid as exercise intensity increases. Concerning the
latter mechanism, muscle fibres vary in the balance of
oxidative versus glycolytic enzymes, that is, ‘aerobic’
versus ‘anaerobic’ metabolism. At low exercise intensities,
fibres that are primarily oxidative are recruited, but as
intensity increases, fibres that rely primarily on glycolytic
pathways are activated, thus increasing the output of
lactic acid [18–20].
However, anaerobiosis at the cellular level and increased
arterial lactate occur above and below a critical arterial
oxygen pressure (PO2), which suggests that other factors
(i.e. glycolytic enzymes) may also be involved [18].
Studies using venous blood lactate measurements were
consistent with a continuous development of acidosis,
rather than a sudden onset of blood lactate accumulation
during progressive exercise [21].
As such, the term AT should be used in a descriptive sense.
The relative contribution of the different sources of lactic
acid may also vary with disease. For example, in heart
failure not only reduced oxygen delivery, but also alteration
in muscle fibre composition and metabolism are present, so
that, as exercise intensity increases, the rate of rise in VO2
starts to decline and the rate of rise in lactate increases
earlier than in normal individuals [12,22].
Regardless of mechanism, the increase in lactic acid,
which appears in the blood as exercise intensity increases,
has important physiological consequences. First, the
build-up in lactic acid reduces the pH of both blood
and interstitial fluid which, in turn, could ultimately
compromise cellular function. Secondly, the reduced pH,
and other events related to the change in pH, likely
stimulate ventilation as the body attempts to buffer the
increased acid by decreases in arterial CO2 pressure
(PCO2). Thirdly, the reduced pH allows a rightward shift
on the Hb/O2 dissociation curve, which increases O2
delivery to the muscles (the so-called ‘Bohr effect’).
Indeed, at the end of the capillary bed of the working
muscles PO2 remains constant while O2 saturation
decreases [23]. Because lactic acid build-up affects
cellular function, the magnitude of the rise in lactate
and the pattern of rise in lactate relative to change in VO2
during exercise may be a useful indicator in exercise
testing. Also, the earlier lactate build-up occurs, the lower
the long-term sustainable VO2.
Clinical applications
The AT demarcates the upper limit of a range of exercise
intensities that can be accomplished almost entirely
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156
European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
aerobically. Whereas work rates below the AT can be
sustained essentially indefinitely, a progressive increase in
work rate above AT is associated with a progressive
decrease in exercise tolerance [24]. In normal individuals,
the AT occurs at about 50–60% VO2max predicted in
sedentary individuals, with a wide range of normal values
extending from 35 to 80% [25]. The AT determination is
age, modality and protocol specific.
AT determination is helpful as an indicator of level of
fitness, for exercise prescription, and to monitor the
effect of physical training [26]. When the AT is not
reached, as in some patients with severe chronic
obstructive airway disease [27], or cannot be determined
from the ventilatory response, as in presence of an
oscillatory pattern, an exercise prescription can still be
established by using as a reference a percentage of peak
work rate, VO2max or HR [28].
A reduction in AT, as in VO2peak, is non-specific: it occurs
in a wide spectrum of clinical conditions/diseases and, as
such, has limited discriminatory ability in distinguishing
between different clinical entities. Values below 40% of
predicted VO2max may indicate a cardiac, pulmonary
(desaturation) or other limitations in O2 supply to the
tissues, or underlying mitochondrial abnormality (e.g.
muscle dysfunction in cardiopulmonary diseases, mitochondrial myopathies).
Measurements
Several methods are available for AT determination and
include invasive (lactic acid and standard bicarbonate)
and non-invasive determinations [ventilatory equivalents
method [VE/VO2, VE/VCO2, end-tidal expiratory oxygen
pressure (PETO2), and end-tidal expiratory CO2 pressure
(PETCO2)], V-slope method, and modified V-slope
method] (Fig. 5).
Although of scientific and physiological importance,
invasive methods have little applicability in clinical
practice. Clinically, increasing lactic acidosis can be
determined non-invasively by observing the pattern of
change in VCO2 and VE relative to VO2 as exercise
intensity increases.
Ventilatory equivalents The ventilatory equivalents method involves the simultaneous analysis of multiple variables (VE/VO2, VE/VCO2, PETO2, and PETCO2). The AT is
then defined by the following events, all of which occur
roughly simultaneously: the VO2 value at which VE/VO2
and PETO2 reach a nadir and thereafter begin to rise
consistently, coinciding with an unchanged VE/VCO2 and
PETCO2 (Fig. 5).
V-slope The AT is identified as the VO2 at which the
change in slope of the relationship of VCO2 to VO2 occurs.
VCO2 increases as a relatively linear function of VO2 early
in an incremental exercise protocol and this slope is
termed S1. As exercise intensity increases, there is a
subsequent increase in the slope, referred to as S2. To
confirm that this change of slope is not occasioned by
hyperventilation, monitoring ventilatory equivalents and
PETCO2 is necessary. Consequently, the ventilatory
equivalents for O2 and end-tidal O2 reach their nadir
and begin to rise in concert with the S1–S2 transition,
without an increase in the ventilatory equivalent for CO2
and/or decrease in end-tidal PCO2 (Figs 4 and 5).
Modified V-slope Due to the complexity of its assessment,
the original V-slope method proposed by Beaver and coworkers [29] has been replaced in most conventional
systems by a simplified approach. The modified V-slope
method, in turn, determines the point of the change in
slope of the relationship of VCO2 versus VO2 and defines
the VO2 above which VCO2 increases faster than VO2
without hyperventilation [16].
When using these methods to detect anaerobic threshold,
it should be kept in mind that there is a good correlation,
but not necessarily a firm physiological link, between ATs
determined invasively and non-invasively, and that
unusual breathing pattern responses to exercise (such
Fig. 5
V-slope
Ventilatory equivalent
3.0
0.0
0.0
3.0
VO2
6.0
50
0
50
0
10
20
VE/VCO2
100
VE/VO2
VCO2
6.0
30
Time
Estimation of the anaerobic threshold according to the modified V-slope method and to the ventilatory equivalent.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 157
as oscillatory breathing) can adversely impact AT
determination.
Because inappropriate increases in VCO2 disproportionate
to increases in metabolic rate (VO2) due to acute
hyperventilation invalidate the non-invasive determination of the AT, it is recommended that both V-slope and
ventilatory equivalents methods be used together (‘dual
methods approach’) as the RER approximates 1.0, to
more accurately determine the AT non-invasively [30].
In CHF a typical reduction in the values of AT is
associated with the fall in exercise tolerance. Its
computation has been proposed not only as adjunctive
information, but also complementary to VO2max because it
measures the sustainable O2 uptake and is an objective
parameter of cardiopulmonary exercise capacity that can
be derived from submaximal exercise testing. Therefore
it is independent of influences such as reduced patient
motivation as well as premature termination of exercise
by the examiner. Conventionally AT values below 40% of
the predicted maximal value of VO2max are considered
abnormal [2]. More recent data have proposed a threshold value of VO2 < 11 ml/kg per min as a negative
prognostic indicator [31,32].
However, in the most advanced stages of the syndrome,
such as class III or IV of the New York Heart Association
(NYHA) functional classification, quite often a clear
value of AT is not identifiable, mainly in the presence of
oscillations. The AT is independent of a patient’s
motivation. When detected, a normal AT with a low
VO2peak suggests submaximal exercise. Because of problems of determination, the AT has never supplanted the
VO2peak as a marker of functional capacity or prognosis in
CHF patients. During most of the daily activity, and in
some cases even at rest, patients’ metabolism is near to,
or even above, the AT [33].
Ventilation
Increased ventilation (VE) during exercise is one of the
primary means by which homeostatically controlled
arterial blood gases and acid–base status is regulated
under conditions of the augmented metabolic demands of
exercising muscles (Fig. 6). Although the mechanisms
that couple VE to gas exchange (metabolic demands)
during exercise are not completely understood, several
indicators of the ventilatory response to exercise may
assess the normality or adequacy of the ventilatory
response.
The most common ventilatory indices assessed during
exercise include changes in total minute ventilation (VE)
and breathing pattern (tidal volume, VT, and respiratory
frequency, f), along with assessment of ventilatory
reserve. Less commonly evaluated are changes in
ventilatory timing (inspiratory time, TI, expiratory time,
TE, and total time, Ttot) and changes in tidal volume
relative to specific lung volumes (e.g. VT/VC).
More recently, changes in inspiratory capacity (IC) and a
more thorough assessment of ventilatory constraint to
exercise have also been utilized. Because ventilation is
a balance between optimization of the mechanics of
breathing and maintenance of gas exchange, many of the
ventilatory indices express these combined elements,
such as the efficiency of ventilation (VE versus VO2 or
VCO2) (Fig. 7).
The rise in VE with exercise is associated with an
increase in both depth (VT) and frequency of breathing
(f). In health, VT increases are primarily responsible for
rises in ventilation during low levels of exercise. As
exercise progresses, both VT and f increase until 70–80%
of peak exercise; thereafter f predominates. VT usually
plateaus at 50–60% of vital capacity (VC); however, there
is considerable variation.
Fig. 6
Normal
200
CHF
VE
VE
120
100
80
40
0
0
200
Watt
400
0
0.0
2.0
4.0
Watt
Ventilation (VE)–work rate relationship in a normal subject (Normal) and in a patient with chronic heart failure (CHF).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
158
European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
Fig. 7
140
Slope: 47
Slope: 29
Slope: 36
120
VE (l/min)
100
80
60
40
Severe CHF
Moderate CHF
Normal
20
0
0
1
2
3
4
5
6
VCO2 (l/min)
Relationship between ventilation (VE) and carbon dioxide production
(VE/VCO2 slope). CHF, chronic heart failure.
In patients with CHF an altered ventilatory pattern has
been described even in the resting state. Spirometric
studies show a reduced forced VC and reduced total lung
capacity, with a relatively preserved forced expiratory vital
capacity [34–36]. This overall restrictive pattern of the
lung has been attributed to increased parenchymal lung
stiffness [37] due to interstitial oedema and consecutive
fibrosis, and possibly to a compressive effect from
cardiomegaly [38]. It is notable that the reduction in
total lung capacity is related to pulmonary capillary wedge
pressure [39,40] and the abnormalities are reversible, at
least in part, by medical treatment [41] or heart
transplantation [42,43], suggesting that they are likely
to be attributable to fluid imbalances rather than
permanent changes such as fibrosis.
In keeping with this concept, in the congestive state,
CHF results in an abnormal increase in pulmonary
capillary wedge pressures, predisposing the lungs to the
early development or aggravation of interstitial oedema
[44,45], which results in an abnormal dynamic reduction
in lung compliance during exercise. These abnormalities
lead to a breathing pattern during exercise that is
characterized by a low tidal volume and an increased
respiratory rate.
Furthermore, the direct impact of cardiomegaly as a
compressive force upon the lungs should not be
forgotten, since it was observed that over two-thirds of
improvement in vital capacity after heart transplantation
could be attributed to a simple reduction in cardiac size
[46]. Despite the presence of restrictive respiratory
changes, ventilatory capacity does not seem to limit
exercise performance in CHF patients, who show an
increase of ventilation during exercise that is about twice
that of normal control subjects [22,47].
The ventilatory capacity can be estimated by multiplying
the forced expiratory volume in one second (FEV1) by the
assumed highest respiratory rate (usually 35–40), which
gives the theoretically achievable minute ventilation,
which is referred to as the maximum voluntary ventilation
(MVV) [48]. To assess whether the ventilatory capacity is
limiting exercise gas exchange, the MVV is related to
actual maximum minute ventilation measured at peak
exercise (peakVE/MVV). This ratio is about 0.6–0.8 for
normal individuals but can increase in patients with
obstructive or restrictive lung disease or in trained
athletes as pulmonary capacity reduces or circulatory
and muscular gas exchange capacity increases. Some
precaution should be used when evaluating the VE/MVV
relationship in patients with poor motivation [49]. In
CHF the peak VE/MVV ratio is reduced compared to that
of normal patients [47]; this may arise from reduction of
muscular and circulatory gas exchange capacity.
It is worthwhile mentioning that for the same amount of
VCO2 produced, the CHF patient presents an higher VE,
and therefore the slope of the relationship of VE in
relation to VCO2 is significantly steeper. Several contributing factors have been investigated to explain the
origin of this high ventilatory drive. Higher blood levels of
metabolic factors resulting from abnormal muscle metabolism (e.g. lactate, hydrogen ion, adenosine, prostaglandin) may trigger the ventilatory centres of the medulla,
either directly and/or indirectly via stimulation of
peripheral and central chemoreflexes and muscle ergoreflex [50]. A positive feedback may come from the general
activation of the sympathetic drive and/or the reduction
in the vagal tone, together with impairment of the carotid
baroreflex, all changes present in CHF syndrome [51].
Regardless of the mechanism, the elevation of the VE/
VCO2 slope is typical of CHF and is associated with poor
prognosis, even in patients with relatively preserved
exercise capacity, namely VO2peak.
Pulmonary diffusion capacity
Gas diffusion is described by Fick’s law:
p
VG ¼ kA=d a= MDp
ð4Þ
where VG is the rate of diffusion of gas, k is a constant
(temperature dependent), A is the membrane area, d is
the thickness of the membrane, a is the solubility of the
gas, M is the molecular mass of the gas and DP is the
difference in pressure of the gas across the membrane.
Accordingly, the alveolar diffusion rate is proportional to
alveolar area, solubility and molecular mass of O2 and CO2
and mean alveolo-capillary difference in the pressures of
O2 and CO2; and is inversely proportional to the
thickness of the alveolo-capillary membrane. Because of
its high solubility, CO2 traverses the alveolo-capillary
membrane about 23 times faster than O2. Hence, any
diffusion limitation of the lungs would primarily affect
the diffusion of O2 but not of CO2. It can be anticipated
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 159
that a theoretical limitation of pulmonary diffusion that
relevantly affects CO2 diffusion must have led to an
impairment of O2 diffusion that would be incompatible
with life.
Besides the size and characteristics of the alveolocapillary membrane, O2 diffusion depends on the
capillary O2 capacity (i.e. the ratio of O2 uptake and the
consecutive change in pressure of O2). This depends on
capillary blood volume, haemoglobin concentration and
the reaction rate between O2 and haemoglobin. The
diffusion capacity of the lungs (DL), therefore, has two
determinants: conductance of the alveolo-capillary membrane resistance (DM) and capillary blood volume (Qc),
provided that haemoglobin concentration is normal.
Consequently, the overall resistance to pulmonary diffusion can be described [52] as:
1=DL ¼ 1=DM þ 1=Qc:
ð5Þ
In patients with CHF the diffusion capacity of the lung
(DL) is reduced and this correlates with heart failure
severity [34,36]. The main contributor is a reduction in
DM [53], whereas capillary blood volume can be variable.
This reduction in DM results from interstitial oedema and
fibrosis [54], both reversible. Treatment with angiotensin-converting enzyme (ACE) inhibitors and anti-aldosteronic drugs can improve diffusion capacity, which is
paralleled by an improvement of the VE/VCO2 and VD/VT
ratios [55].
However, there is evidence that DM remains low even
years after heart transplantation [56]. The question of
whether this reduction of diffusion capacity does
contribute to exercise limitation and the enhanced
ventilatory response to exercise in CHF is still an
unresolved issue [57]. DM closely correlates with peak
oxygen uptake [58], but on the one hand, it has been
shown that it may decreases during exercise, possibly as a
result of the formation of interstitial oedema [59]. On the
other hand, DM may increase, but the extent of this
increase is very limited and is accompanied by an increase
in VC so that DL remains constant [60].
However, diffusing capacity does not seem to limit
alveolar oxygen consumption, that is, arterial hypoxaemia
is not a typical finding in CHF [61]. Therefore, the
correlations between diffusion capacity (or DM) and
markers of exercise capacity might not reveal a causal
relationship but reflect a common determinant, namely
poor haemodynamic response to exercise, with high left
ventricular filling pressures and consecutive increases in
pulmonary capillary pressure.
results in a low pulmonary artery pressure, which only
mildly increases when cardiac output increases. Apart
from this global haemodynamic characteristic, the regional distribution of blood flow within the lungs is tightly
regulated by small pre-capillary resistance vessels. A
major regulator of regional flow distribution is hypoxic
vasoconstriction (Euler–Liljestrand mechanism); a fall in
alveolar pressure of O2 results in increased vascular tone
and reduced blood flow through the related lung
compartment [63,64]. This leads to a matching between
pulmonary ventilation and perfusion, which minimizes
intrapulmonary shunt (i.e. perfusion relatively large for
the corresponding ventilation and therefore small alveolar
spaces, favouring pulmonary-venous PO2) and dead space
ventilation (i.e. perfusion relatively small for the corresponding ventilation). Numerous vasodilators (nitric
oxide, prostacyclin) [65–68] and vasoconstrictors (thromboxane, endothelin-1) [69–71] are involved in this
regulatory process.
In CHF increased left ventricular filling pressures lead to
pulmonary venous hypertension. This increase in pulmonary artery pressure is further augmented by an
increase in pulmonary vascular resistance [62]. Haemodynamic studies in patients with mitral stenosis before
and after mitral valve replacement show a prompt
reduction in pulmonary vascular resistance after normalization of pulmonary venous pressures [72,73], which
suggests that the increase in pulmonary vascular tone is a
direct response to the increase in pulmonary venous
pressures. The increase in vascular tone results from both
an impairment of basal vasodilator activity and augmented vasopressor stimuli. It has been shown that the basal
release of nitric oxide, a potent vasodilator [66], from the
pulmonary vascular endothelium is reduced in patients
with heart failure and secondary pulmonary hypertension
[74–76], but can be stimulated by acetylcholine. There is
reduced prostacyclin synthesis with a concomitant
increase in the synthesis of thromboxane [69]. Endothelin-1 levels are elevated in heart failure and, in conjunction
with the downregulation of pulmonary ET-B receptors, this
produces pulmonary vasoconstriction [70,77].
These mechanisms lead not only to an increase in overall
pulmonary vascular resistance, but also to an impairment
of regional pulmonary blood flow distribution, as evident
from scintigraphic studies [78]. This leads to an
irregularity of pulmonary perfusion despite normal distribution of ventilation. This is referred to as pulmonary
ventilation–perfusion mismatch. The failure to adequately
reduce this mismatch during exercise may contribute to
the low exercise capacity in patients with CHF [79].
Pulmonary perfusion
The pulmonary circulation is characterized by a low
vascular tone with a further reduction of pulmonary
vascular resistance when blood flow increases [62]. This
Dead space ventilation
The theoretical volume of gas in the airways and the
lungs, which does not contribute to gas exchange,
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160
European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
constitutes the dead space ventilation (VD). It can be
divided into ‘serial dead space’ (previously called
‘anatomical dead space’) and ‘alveolar dead space’. Serial
dead space largely consists of the volume of the mouth,
pharynx and large airways; its absolute volume might be
relatively steady with time within any one patient.
Alveolar dead space arises because perfusion of alveoli is
insufficient for, or insufficiently well matched to, alveolar
ventilation (VA); its absolute volume normally falls with
exercise (if cardiac output rises sharply and in a welldistributed fashion). But alveolar dead space ventilation
could also rise if cardiac output fails to rise adequately or
becomes maldistributed.
exercise, VE and VCO2 are linearly related until the RER,
where VE increases disproportionately to VCO2. The slope
of this relationship, before the RER, reflects the gain of
chemoreceptors that triggers ventilation in response to
changes in PCO2 in the blood. The VE/VCO2 slope has
been related to increased pulmonary dead space, to the
decrease of pulmonary blood flow, and to the activation of
ergoreceptors originating from the muscle.
VD=VT ¼ ðPCO 2 PETCO 2 Þ=PCO 2 VD valve=VT ð6Þ
This slope is increased in CHF: normal values are
between 20 and 30 while in CHF it can reach values
around 80 (Fig. 7). The VE/VCO2 is improved by training
and by treatment. VE/VCO2 slope appeared to better
predict prognosis than peak VO2, particularly in two
situations: (1) in the case of submaximal exercise; (2) in
the case of beta-blocker therapy, where prognosis
improves with treatment whereas peak VO2 generally
remains unchanged or increases only slightly and VE/VCO2
slope is decreased [86].
where VD valve represents the mouthpiece and valve
dead space volume. Non-invasive assessment of PCO2
estimated by PETCO2, is not reliable and underestimates
the real value, calculated by arterial sampling.
Whether the VE/VCO2 slope should be calculated across
the overall data or only until the RQ is still controversial
[87]: using all points seems to increase the prognostic
value [88].
VD/VT, the ratio between physiological dead space and
tidal volume, constitutes an index of this mismatching
between ventilation and perfusion, and it may be
calculated according to the Bohr equation:
At rest the value of VD/VT ranges between 0.3 and 0.5,
but on exercise it is reduced to 0.2. In patients with lung
diseases, due to both ventilatory or perfusion abnormalities of the alveoli, this ratio is elevated at rest and does
not fall on exercise [80].
Patients with CHF may fail to appropriately reduce their
VD/VT ratio during exercise, which may contribute to
exercise hyperpnoea [81]. Although the serial and alveolar
components have not been measured directly, they both
seem to be involved in this phenomenon. Patients with
more severe heart failure had a more rapid and shallow
breathing pattern, as well as an increased difference
between end-tidal and arterial PCO2, which suggests
increased alveolar dead space. The increase in alveolar
dead space has to arise from mechanisms that impede the
improvement of ventilation/perfusion matching during
exercise. The correlation of the VE/VCO2 slope with
severity of pulmonary hypertension [82] and cardiac
output [83] suggests that pulmonary vasoconstriction and
low pulmonary blood flow are potential contributors.
Abnormal regulation of pulmonary vascular tone could
lead to an uneven flow distribution through the lungs.
Alternatively, assuming that the increase in cardiac
output is a major facilitator of even blood flow distribution, a low cardiac output would lead to less of an
improvement in blood flow distribution during exercise.
VE/VCO2 slope
The VE/VCO2 slope has emerged in recent years as a very
popular parameter in patients with CHF and one of the
most powerful CHF prognosticators [81,84,85]. During
Another slope, the oxygen uptake efficiency slope,
relating linearly VO2 and the logarithm of VE during
exercise, is another interesting parameter obtainable in
cases of submaximal exercise [89]. It is decreased in heart
failure.
Cardiac output
Cardiac output (CO) increases with exercise to support
the increasing metabolic demands of the tissues. In
normal subjects, according to the Fick equation [equation
(1)], CO is a linear function of VO2 [90].
Increases in CO are initially accomplished by increases in
SV and HR, and then at moderate to high-intensity
exercise almost exclusively by increases in HR. The
evaluation of HR response yields an estimation of cardiac
function during exercise. The increase in cardiac output
is largely driven by vagal withdrawal and by increases in
either circulating or neurally produced catecholamines.
Indirect measurement of cardiac function on exercise
(HR, HR–VO2 relationship, O2 pulse), assessed during
CPET testing, has been proposed.
Heart rate (HR)
According to the Fick equation, it can be derived that HR
measurement should be a simple guide to cardiac
function during exercise, given the modest changes in
SV. In healthy subjects, heart rate increases nearly linearly
with increasing VO2 (Fig. 8). Increases in HR are initially
mediated by a decrease in parasympathetic activity
(vagal withdrawal) and, subsequently, almost exclusively
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 161
Fig. 8
VO2 30
240
160
20
160
80
10
80
HR
240
VO2 30
HR
HR
20
10
VO2
0
0
200
Work
400
0
0
100
Work
200
Heart rate (HR)- and O2 pulse–work rate relationships in a normal subject (Normal) and in a patient with chronic heart failure (CHF).
by increased sympathetic activity. Achievement of agepredicted values for maximal HR during exercise is often
used as a reflection of maximal or near maximal effort,
and presumably signals the achievement of VO2max.
However, the use of this marker as a strict exercise
end-point is not recommended [8]. Considerable variability (10–15 beats/min) within an age group is noted
when available estimates of maximal HR are used, and as
such, may complicate interpretation, as might the effects
of bradycardic medication.
HR–VO2 relationship
This relationship is often non-linear at low work rates for
upright exercise, becoming relatively linear as work rate
increases to maximum. It can be described by the slope
and position of the regression line. The slope of the
HR–VO2 relationship is a function of the subject’s SV and
C(A – V)O2 (see below). In the absence of anaemia,
shunt, or hypoxia, the higher the SV, the lower the HR
and, typically, its rate of change. HR at a given VO2 is
higher than normal in patients with lung disease,
implying that SV must be lower, because cardiac output
is similar to that of normal subjects. This may reflect
deconditioning or relative unfitness, ventilatory limitation to exercise and, possibly, the haemodynamic
consequences of dynamic hyperinflation. Patients with
reduced O2 delivery due to reduced O2 content
(hypoxaemia, anaemia, carboxyhaemoglobin, etc.), patients with abnormal O2 utilization (metabolic myopathy), as well as patients with deconditioning, may also
have an upward and steep HR–VO2 relationship with
(near) attainment of maximal heart rate.
Oxygen pulse (VO2/HR)
The ratio of VO2 to HR is conventionally termed the
‘oxygen pulse’ and reflects the amount of O2 extracted
per heart beat. The O2 pulse has been used as an
estimator of stroke volume during exercise [2]; however,
this remains controversial, especially in patients who
desaturate. According to the modified Fick equation, the
O2 pulse is numerically equal to the product of SV and
the arterial-to-mixed venous O2 content difference,
C(A – V)O2.
The O2 pulse normally increases with incremental
exercise because of increases in both SV and O2
extraction. At a near maximal/maximal work rate, in
which C(A – V)O2 is assumed to be maximal and
relatively constant, the pattern of change of the O2 pulse
will represent the concomitant pattern of change of the
SV, as long as the previous assumption is correct. The
basic profile of the O2 pulse over the range in
which VO2 increases linearly with HR appears to be
hyperbolic, with a rapid rise at low work rates followed by
a slow approach to an asymptotic value. A low, unchanging, flat O2 pulse with increasing work rate may
therefore be interpreted as resulting from a reduced SV,
and/or as a failure for further skeletal muscle
O2 extraction, and/or occurrence of exercise-induced
ischaemia. A low O2 pulse therefore may reflect
deconditioning, cardiovascular disease, and early exercise
limitation due to ventilatory constraint, lung diseases or
symptoms.
In CHF, impaired CO response on exercise is determined
by alteration in all the above-mentioned indices. Chronotropic incompetence to exercise is charged with poor
prognosis: the CHF patients with HR at peak exercise < 135 beats/min have a lower survival rate with respect
to those with HR > 44 beats/min [31]. Similarly for
the HR–VO2 and oxygen pulse, down-slopes of these
relationships are present in CHF: during exercise the
progressive rise in HR is not adequately reflected by a
proportional rise in VO2. However, these changes are not
specific for CHF and many other factors may affect these
patterns on exercise, for example, the presence of atrioventricular block or therapy (beta-blockade, calciumchannel blockers).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
162 European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
Blood pressure response
As exercise intensity increases, reflex control of distribution of cardiac output causes some characteristic changes
in blood pressure and vascular resistance [91]. In working
muscle, there are local mediators that cause intense
vasodilation that increases blood flow to support metabolic demands. In addition, non-working muscles are
vasoconstricted from reflex increases in sympathetic
nerve activity [92]. The net result is a fall in systemic
vascular resistance, but systolic blood pressure typically
rises progressively with an increase in VO2. Diastolic blood
pressure typically remains constant or may decline
slightly if left heart function keeps up with the increases
in cardiac output. Abnormal patterns of blood pressure
response include excessive rise, reduced rise, or a fall.
An excessive rise in blood pressure is often seen in
patients with known resting hypertension, but an
abnormal rise with exercise in the face of normal resting
blood pressure is also indicative of abnormal blood
pressure control. If blood pressure does not increase with
exercise, or in fact declines, a cardiac limitation or
abnormality of sympathetic control of blood pressure is
strongly suggested. If blood pressure falls as exercise
intensity increases, the exercise test should be terminated immediately, as such a response could indicate
serious abnormality such as heart failure, ischaemia, or
restriction to blood flow, such as aortic stenosis,
pulmonary vascular disease, or central venous obstruction.
8
9
10
11
12
13
14
15
16
17
18
19
20
Like the other indices of CO, the blood pressure response
is impaired in CHF, with an impaired rise during
progressive exercise. A systolic blood pressure value
< 120 mmHg is associated with exercise intolerance
(VO2peak r 14 ml/kg per min) and reflects a poor prognosis [93]. The same limitations affecting the interpretation of the above indices of CO, also apply to the blood
pressure response.
References
1
2
3
4
5
6
7
American Thoracic Society; American College of Chest Physicians. ATS/
ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit
Care Med 2003; 167:211–277.
Wasserman K, Hansen JE, Sue DY, Whipp BJ, Casaburi R. Principles of
exercise testing and interpretation: including pathophysiology and clinical
applications. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.
Weisman IM, Zeballos RJ. Cardiopulmonary exercise testing: the need for
standardization. Pulm Perspect 1992; 9:5–8.
Rickli H, Kiowski W, Brehm M, Weilenmann D, Schalcher C, Bernheim A,
et al. Combining low-intensity and maximal exercise test results improves
prognostic prediction in chronic heart failure. J Am Coll Cardiol 2003;
42:116–122.
Cohen-Solal A, Chabernaud J, Gourgon R. Comparison of oxygen uptake
during bicycle exercise in patients with chronic heart failure and in normal
subjects. J Am Coll Cardiol 1990; 16:80–85.
Koike A, Itoh H, Kato M, Sawada H, Aizawa T, Fu LT, Watanabe H.
Prognostic power of ventilatory responses during submaximal exercise in
patients with chronic heart disease. Chest 2002; 121:1581–1588.
Myers J, Walsh D, Buchanan N, Froelicher VF. Can maximal cardiopulmonary
capacity be recognized by a plateau in oxygen uptake? Chest 1989;
96:1312–1316.
21
22
23
24
25
26
27
28
29
Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF,
et al. ACC/AHA 2002 guideline update for exercise testing: summary article.
A report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee to Update the 1997 Exercise
Testing Guidelines). J Am Coll Cardiol 2002; 40:1531–1540.
Garrard CS, Emmons C. The reproducibility of the respiratory responses to
maximum exercise. Respiration 1986; 49:94–100.
Wilson RC, Jones PW. Long-term reproducibility of Borg Scale estimates of
breathlessness during exercise. Clin Sci 1991; 80:309–312.
Meyer K, Westbrook S, Schwaibold M, Hajric R, Peters K, Roskamm H.
Short-term reproducibility of cardiopulmonary measurements during
exercise testing in patients with severe chronic heart failure. Am Heart J
1997; 134:20–26.
Piepoli M, Scott AS, Capucci A, Coats AJS. Skeletal muscle training in
chronic heart failure. Acta Physiol Scand 2001; 171:295–303.
Corra U, Mezzani A, Bosimini E, Giannuzzi P. Cardiopulmonary exercise
testing and prognosis in chronic heart failure: a prognosticating algorithm for
the individual patient. Chest 2004; 126:942–950.
Cohen-Solal A, Laperche T, Morvan D, Geneves M, Caviezel B, Gourgon R.
Prolonged kinetics of recovery of oxygen consumption and ventilatory
variables after maximal graded exercise in patients with chronic heart failure.
Analysis with gas exchange and NMR spectroscopy study. Circulation
1995; 91:2924–2932.
Cohen-Solal A, Tabet J, Logeart D, Bourgoin P, Tokmakova M, Dahan M.
A non-invasively determined surrogate of cardiac power (‘circulatory power’)
at peak exercise is a powerful prognostic factor in chronic heart failure.
Eur Heart J 2002; 23:806–814.
Sue DY, Wasserman K, Moricca RB, Casaburi R. Metabolic acidosis during
exercise in patients with chronic obstructive pulmonary disease. Use of the
V-slope method for anaerobic threshold determination. Chest 1988;
94:931–938.
Simonton CA, Higginbotham MB, Cobb FR. The ventilatory threshold:
quantitative analysis of reproducibility and relation to arterial lactate
concentration in normal subjects and in patients with chronic congestive
heart failure. Am J Cardiol 1988; 62:100–107.
Myers J, Ashley E. Dangerous curves: a perspective on exercise, lactate, and
the anaerobic threshold. Chest 1997; 111:787–795.
Hughson RL, Weisiger KH, Swanson GD. Blood lactate concentration
increases as a continuous function in progressive exercise. J Appl Physiol
1987; 62:1975–1981.
Dempsey JA, Adams L, Ainsworth DM, Fregosi RF, Gallagher CG, Guz A,
et al. Airway, lung and respiratory muscle function during exercise. In: Rowell
LB, Shepard JT, editors. Handbook of physiology. Section 12. Exercise:
regulation and integration of multiple systems. New York: Oxford University
Press; 1996. pp. 448–514.
Dennis SC, Noakes TD, Bosch AN. Ventilation and blood lactate increase
exponentially during incremental exercise. J Sports Sci 1992; 10:437–449.
Wasserman K, Zhang YY, Gitt A, Belardinelli R, Koike A, Lubarsky L,
Agostoni PG. Lung function and exercise gas exchange in chronic heart
failure. Circulation 1997; 96:2221–2227.
Agostoni PG, Wasserman K, Perego GB, Marenzi GC, Guazzi M, Assanelli
E, et al. Oxygen transport to muscle during exercise in chronic congestive
heart failure secondary to idiopathic dilated cardiomyopathy. Am J Cardiol
1997; 79:1120–1124.
Sullivan CS, Casaburi R, Storer TW, Wasserman K. Non-invasive prediction
of blood lactate response to constant power outputs from incremental
exercise tests. Eur J Appl Physiol Occup Physiol 1995; 71:349–354.
European Respiratory Society. Clinical exercise testing with reference to
lung diseases: indications, standardization and interpretation strategies.
ERS Task Force on Standardization of Clinical Exercise Testing. Eur Respir J
1997; 10:2662–2689.
Casaburi R, Patessio A, Ioli F, Zanaboni S, Donner CF, Wasserman K.
Reductions in exercise lactic acidosis and ventilation as a result of exercise
training in patients with obstructive lung disease. Am Rev Respir Dis 1991;
143:9–18.
Casaburi R, Porszasz J, Burns MR, Carithers ER, Chang RS, Cooper CB.
Physiologic benefits of exercise training in rehabilitation of patients with
severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med
1997; 155:1541–1551.
American Association of Cardiovascular and Pulmonary Rehabilitation.
Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based guidelines.
ACCP/AACVPR Pulmonary Rehabilitation Guidelines Panel. Chest 1997;
112:1363–1396.
Beaver WL, Wasserman K, Whipp BJ. A new method for detecting
anaerobic threshold by gas exchange. J Appl Physiol 1986; 60:
2020–2027.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cardiopulmonary exercise and heart failure: Part I 163
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
Zeballos RJ, Weisman IM. Behind the scenes of cardiopulmonary exercise
testing. Clin Chest Med 1994; 15:193–213.
Myers J, Gullestad L, Vagelos R, Do D, Bellin D, Ross H, Fowler MB. Clinical,
hemodynamic, and cardiopulmonary exercise test determinants of survival in
patients referred for evaluation of heart failure. Ann Intern Med 1998;
129:286–293.
Gitt AK, Wasserman K, Kilkowski C, Kleemann T, Kilkowski A, Bangert M,
et al. Exercise anaerobic threshold and ventilatory efficiency identify heart
failure patients for high risk of early death. Circulation 2002; 106:
3079–3084.
Opasich C, Pinna GD, Bobbio M, Sisti M, Demichelis B, Febo O, et al. Peak
exercise oxygen consumption in chronic heart failure: toward efficient use in
the individual patient. J Am Coll Cardiol 1998; 31:766–775.
Collins JV, Clark TJH, Brown DJ. Airway function in healthy subjects and
patients with left heart disease. Clin Sci Mol Med 1975; 49:
217–228.
Wright RS, Levine MS, Bellamy PE, Simmons MS, Batra P, Stevenson LW.
Ventilatory and diffusion abnormalities in potential heart transplant
recipients. Chest 1990; 98:816–820.
Ewert R, Wensel R, Bettmann M, Spiegelsberger S, Grauhan O, Hummel M,
Hetzer R. Ventilatory and diffusion abnormalities in long-term survivors after
orthotopic heart transplantation. Chest 1999; 115:1305–1311.
Agostoni P, Pellegrino R, Conca C, Rodarte JR, Brusasco V. Exercise in
chronic heart failure: relationships to lung stiffness and expiratory flow
limitation. J Appl Physiol 2002; 92:1409–1416.
Agostoni P, Cattadori G, Guazzi M, Melzi G, Lomanto M, De Vita S, et al.
Cardiomegaly as a possible cause of lung dysfunction in heart failure
patients. Am Heart J 2000; 140:E 24.
Frank NR, Lyons HA, Siebens AA, Nealon TF. Pulmonary compliance in
patients with cardiac disease. Am J Med 1957; 22:516–521.
Ries AL, Gregoratos G, Friedman PJ, Clausen JL. Pulmonary function test in
the detection of left heart failure: correlation with pulmonary artery wedge
pressure. Respiration 1986; 49:241–250.
Faggiano P, Lombardi C, Sorgato A, Ghizzoni G, Spedini C, Rusconi C.
Pulmonary function tests in patients with congestive heart failure: effects of
medical therapy. Cardiology 1993; 83:30–35.
Hosenpud JD, Stibolt TA, Atwal K, Shelley D. Abnormal pulmonary function
specifically related to congestive heart failure: comparison of patients before
and after cardiac transplantation. Am J Med 1990; 88:493–496.
Ravenscraft SA, Gross CR, Kubo SH, Olivari MT, Shunway SJ, Bolman RE
III, Hertz MI. Pulmonary function after successful heart transplantation.
Chest 1993; 103:54–58.
Gazetopoulos N, Davies H, Oliver C, Deuchar D. Ventilation and
haemodynamics in heart disease. Br Heart J 1966; 28:1–15.
Szidon JP. Pathophysiology of the congested lung. Cardiol Clinics 1989;
7:39–48.
Hosenpud JD, Stibolt TA, Atwal K, Shelley D. Abnormal pulmonary function
specifically related to congestive heart failure: comparison of patients before
and after cardiac transplantation. Am J Med 1990; 88:493–496.
Clark AL, Davies LC, Francis DP, Coats AJS. Ventilatory capacity in patients
with chronic stable heart failure. Eur J Heart Failure 2000; 2:47–51.
Wasserman K. Breathing reserve, tidal volume, and breathing frequency at
maximum exercise. In: Wasserman K, Hansen JE, Sue DY, Casaburi R,
Whipp BJ. editors. Principles of exercise testing and interpretation. 3rd ed.
Baltimore: Lippincott Williams & Wilkins; 1999. pp. 155–156.
Agostoni PG, Butler J. Cardiac evaluation. In: Murray N, editor. Textbook of
respiratory disease, 2nd ed. Philadelphia: WB Saunders; 1994.
pp. 943–962.
Clark AL, Poole-Wilson PA, Coats AJ. Exercise limitation in chronic heart
failure: central role of the periphery. J Am Coll Cardiol 1996; 28:
1092–1102.
Ponikowski P, Francis DP, Piepoli MF, Davies LC, Chua TP, Davos CH, et al.
Enhanced ventilatory response to exercise in patients with chronic heart
failure and preserved exercise tolerance: marker of abnormal
cardiorespiratory reflex control and predictor of poor prognosis. Circulation
2001; 103:967–972.
Roughton FJ, Forster FE. Relative importance of diffusion and chemical
reaction rates in determining rate of exchange of gases in human lung, with
special reference to true diffusing capacity of blood in the lung capillaries.
J Appl Physiol 1957; 11:290–302.
Puri S, Baker BL, Oakley CM, Hughes JMB, Cleland JG. Increased alveolar/
capillary membrane resistance to gas transfer in patients with chronic heart
failure. Br Heart J 1994; 72:140–144.
Guazzi M. Alveolar-capillary membrane dysfunction in chronic heart failure:
pathophysiology and therapeutic implications. Clin Sci 2000;
98:633–641.
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
Agostoni P, Magini A, Andreini D, Contini M, Apostolo A, Bussotti M, et al.
Spironolactone improves lung diffusion in chronic heart failure. Eur Heart J
2005; 26: 159–164.
Ewert R, Wensel R, Bettmann M, Spiegelsberger S, Grauhan O, Hummel M,
Hetzer R. Ventilatory and diffusion abnormalities in long-term survivors after
orthotopic heart transplantation. Chest 1999; 115:1305–1311.
Agostoni P, Bussotti M, Palermo P, Guazzi M. Does lung diffusion
impairment affect exercise capacity in patients with heart failure? Heart
2002; 88:453–459.
Puri S, Baker BL, Dutka DP, Oakley CM, Hughes JMB, Cleland JG.
Reduced alveolar-capillary membrane diffusing capacity in chronic heart
failure: its pathophysiological relevance and relationship to exercise
performance. Circulation 1995; 91:2769–2774.
Agostani P, Cattadori G, Bianchi M, Wasserman K. Exercise-induced
pulmonary edema in heart failure. Circulation 2003; 108: 2666–2671.
Puri S, Baker L, Dutka DP, et al. Reduced alveolar-capillary membrane
diffusing capacity in chronic heart failure. Circulation 1995; 91:2769–2777.
Rubin SA, Brown HV. Ventilation and gas exchange during exercise in
severe chronic heart failure. Am Rev Respir Dis 1984; 129:S63–S64.
Grossman W, Braunwald E. Pulmonary hypertension. In: Braunwald E,
editor. Heart disease. Philadelphia: WB Saunders; 1992. pp. 790–791.
Liljestrand G. Chemical control of the distribution of the pulmonary blood
flow. Acta Physiol Scand 1958; 44:216–240.
Grimminger F, Spriestersbach R, Weissmann N, Walmrath D, Seeger W.
Nitric oxide generation and hypoxic vasoconstriction in buffer-perfused
rabbit lungs. J Appl Physiol 1995; 78:1509–1515.
Cremona G, Dinh Xuan AT and Higenbottam TW. Endothelium-derived
relaxing factor and the pulmonary circulation. Lung 1991; 169:185–202.
Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the
biologic activity of endothelium-derived relaxing factor. Nature 1987; 327:
524–526.
Stamler JS, Loh E, Roddy M-A, Currie KE, Creager MA. Nitric oxide
regulates basal systemic and pulmonary vascular resistance in healthy
humans. Circulation 1994; 89: 2035–2040.
Vanhoutte PM. Other endothelium-derived vasoactive factors. Circulation
1993; 87:V-9–V-17.
Christman BW, McPherson CD, Newman JH, King GA, Bernard GR,
Groves BM, Loyd JE. An imbalance between the excretion of thromboxane
and prostacyclin metabolites in pulmonary hypertension. N Engl J Med
1992; 327:70–75.
Cody RJ, Haas GJ, Binkley PhF, Capers Qu, Kelley R. Plasma endothelin
correlates with the extent of pulmonary hypertension in patients with chronic
congestive heart failure. Circulation 1992; 85:504–509.
Spieker LE, Noll G, Ruschitzka FT, Lüscher T. Endothelin receptor
antagonists in congestive heart failure: a new therapeutic principle for the
future? J Am Coll Cardiol 2001; 37:1493–1505.
Dalen JE, Matloff JM, Evans GL, Hoppin FG, Bhardwaj P, Harken DE,
Dexter L. Early reduction of pulmonary resistance after mitral valve
replacement. N Engl J Med 1967; 277:387–394.
Braunwald E, Braunwald NS, Ross J, Morrow AG. Effects of mitral valve
replacement on pulmonary vascular dynamics of patients with pulmonary
hypertension. N Engl J Med 1965; 273:509–514.
Wensel R, Opitz CF, Kleber FX. Acetylcholine but not sodium nitroprusside
exerts vasodilation in pulmonary hypertension secondary to chronic
congestive heart failure. J Heart Lung Transplant 1999; 18:877–883.
Cooper CJ, Landzberg MJ, Anderson TJ, Charbonneau F, Creager MA,
Ganz P, Selwyn AP. Role of nitric oxide in the local regulation of pulmonary
vascular resistance in humans. Circulation 1996; 93:266–271.
Cooper CJ, Jevnikar FW, Walsh T, Dickinson J, Mouhaffel A, Selwyn AP. The
influence of basal nitric oxide activity on pulmonary vascular resistance in
patients with congestive heart failure. Am J Cardiol 1998; 82:609–614.
Sasaki T, Noguchi T, Komamura K, Nishikimi T, Yoshikawa H, Miyatake K.
Differential roles of endothelin-1 in the development of secondary pulmonary
hypertension in patients with left heart failure with or without acute
exacerbation. J Cardiac Failure 1999; 5:38–45.
Wada O, Asanoi H, Miyagi K, Ishizaka S, Kameyama T, Seto H, Sasayama S.
Importance of abnormal lung perfusion in excessive exercise ventilation in
chronic heart failure. Am Heart J 1993; 125:790–798.
Uren NG, Davies SW, Agnew JE, Irwin AG, Jordan SL, Hilson AJ, Lipkin DP.
Reduction of mismatch of global ventilation and perfusion on exercise is
related to exercise capacity in chronic heart failure. Br Heart J 1993;
70:241–246.
Wasserman K. Normal values, Physiologic dead space/tidal volume ratio.
In: Wasserman K, Hansen JE, Sue DY, Casaburi R, Whipp BJ, editors.
Principles of exercise testing and interpretation. 3rd ed. Baltimore:
Lippincott Williams & Wilkins; 1999. pp. 157–158.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
164
European Journal of Cardiovascular Prevention and Rehabilitation 2006, Vol 13 No 2
81 Metra M, Dei Cas L, Panina G, Visioli O. Exercise hyperventilation chronic
congestive heart failure, and its relation to functional capacity and
hemodynamics. Am J Cardiol 1992; 70:622–628.
82 Reindl I, Wernecke KD, Opitz C, Wensel R, Konig D, Dengler T, et al.
Impaired ventilatory efficiency in chronic heart failure: possible role of
pulmonary vasoconstriction. Am Heart J 1998; 136:778–785.
83 Tanabe Y, Hosaka Y, Ito M, Ito E, Suzuki K. Significance of end-tidal
P(CO(2)) response to exercise and its relation to functional
capacity in patients with chronic heart failure. Chest 2001; 119:
811–817.
84 Chua TP, Ponikowski P, Harrington D, Anker SD, Webb-Peploe K, Clark AL,
et al. Clinical correlates and prognostic significance of the ventilatory
response to exercise in chronic heart failure. J Am Coll Cardiol 1997;
29:1585–1590.
85 Francis DP, Shamim W, Davies CL, Piepoli MF, Ponikowski P, Anker SD,
Coats AJ. Cardiopulmonary exercise testing for prognosis in chronic heart
failure: continuous and independent prognostic value from VE/VCO2 slope
and peak VO2. Eur Heart J 2002; 21:154–161.
86 Agostoni P, Guazzi M, Bussotti M, De Vita S, Palermo P. Carvedilol reduces
the inappropriate increase of ventilation during exercise in heart failure
patients. Chest 2002; 122:2062–2067.
87 Arena R, Humphrey R, Peberdy MA. Prognostic ability of VE/VCO2 slope
calculations using different exercise test time intervals in subjects with heart
failure. Eur J Cardiovasc Prev Rehabil 2003; 10:463–468.
88 Tabet JY, Beauvais F, Thabut G, Tartiere JM, Logeart D, Cohen-Solal A.
A critical appraisal of the prognostic value of the VE/VCO2 slope in
chronic heart failure. Eur J Cardiovasc Prev Rehabil 2003; 10:
267–272.
89 Baba R, Nagashima M, Goto M, Nagano Y, Yokota M, Tauchi N, Nishibata K.
Oxygen uptake efficiency slope: a new index of cardiorespiratory functional
reserve derived from the relation between oxygen uptake and minute
ventilation during incremental exercise. J Am Coll Cardiol 1996; 28:
1567–1572.
90
91
92
93
Stringer WW, Hansen JE, Wasserman K. Cardiac output estimated
noninvasively from oxygen uptake during exercise. J Appl Physiol 1997;
82:908–912.
Perloff D, Grim C, Flack J, Frohlich ED, Hill M, McDonald M, Morgenstern B.
Human blood pressure determination by sphygmomanometry. Circulation
1993; 88:2460–2470.
Piepoli M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, Coats AJ.
Contribution of muscle afferents to the hemodynamic, autonomic, and
ventilatory responses to exercise in patients with chronic heart failure:
effects of physical training. Circulation 1996; 93:940–952.
Osada N, Chaitman BR, Miller LW, Yip D, Cishek MB, Wolford TL, Donohue
TJ. Cardiopulmonary exercise testing identifies low risk patients with heart
failure and severely impaired exercise capacity considered for heart
transplantation. J Am Coll Cardiol 1998; 31:577–582.
Appendix
Writing Committee
Massimo F. Piepoli and Ugo Corrà (Chairmen) (Italy),
Pier Giuseppe Agostoni (Italy), Romualdo Belardinelli
(Italy), Alain Cohen-Solal (France), Rainer Hambrecht
(Germany) and Luc Vanhees (Belgium).
Document Reviewers Committee
Hans Björnstad (Norway), Andrew J.S. Coats (Australia),
Darrel P. Francis (UK), Pantaleo Giannuzzi (Italy), Marco
Guazzi (Italy), Marco Metra (Italy), Alessandro Mezzani
(Italy), Piotr Ponikowski (Poland) and Hugo Saner
(Switzerland).
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.